Labels

Wednesday, September 16, 2009

Part of the reason behind Sanofi-Aventis' success in emerging markets is its aggressive strategy in China, where it currently has 3,500 employees in vaccines, R&D, commercial operations and manufacturing. Sanofi-Aventis China R&D Head Frank Jiang sat down with PharmAsia News editor Tamra Sami to discuss the environment in China and how Sanofi is approaching R&D there.

Biotechs are blooming in China, and the industry is predicting that Shanghai will look much like San Diego in a few years, Sanofi-Aventis China R&D Head Frank Jiang told PharmAsia News.

With the cost of developing a drug now $1 billion, and half of drugs failing in late-stage trials, there is an even greater need to break down traditional "linear" drug development and come up with different models. Big Pharma is increasingly looking outside of its walls for sources of innovation both for drug development and for biomedical diagnostic tools.

"But we need a way to match new scientific tools and approaches with clinical design - not the kind of clinical design we do today," Jiang stressed.

"Biotech in China is blooming, but we have not seen any global product coming out of China, and the challenge for China biotechs is that the best science remains in the universities and academic institutions, many being government-supported programs," Jiang said.

Perhaps an even bigger drawback for Chinese biotechs is the Chinese culture itself, which can be risk-averse. Most drugs fail, "so you need to have vision, resource, infrastructure and the patience to see the outcomes," he said.

Also, the ability to fail a compound earlier is an important advance for the industry.

Most multinational pharma companies now include China in their global drug development programs, and China is playing an increasingly important role in companies' R&D strategies, partly because of the country's dynamic growth and ability to be more adaptive.

"This is the best time to work here - change is so fast; we are still building, which is somewhat different from Japan," Jiang said.

China contributes close to 10 percent of Sanofi's global patient population for its clinical trials. China's State FDA regulations specify that for a drug to be approved in China, there must be a minimum of Chinese patients - in most cases 240 - in a Phase III trial, Jiang said.

He noted that China has participated in several global mega trials, including one with a total patient population reaching 21,000.

It would be difficult to show any statistical significance with 240 patients out of a total patient population of 21,000, but if you stack the patient population to include early responders using predictive tools such as biomarkers, you can shrink the sample size, he said.

"We are working very closely with SFDA and [the agency] is very interested in how to utilize adaptive trial designs," he said, noting that during a workshop presentation in March, SFDA Center for Drug Evaluation reviewers were especially interested in how to use biomarkers to identify those early responders "so you can decrease the sample size and get a response in a much larger differential."

Adaptive trial designs use accumulating data during the study and then look at that data at pre-determined interim points, which then determine how the latter part of the study is modified without undermining the validity and integrity of the design. Those modifications, however, are not ad hoc - they are prospectively built into the trial design.

"If an interim look shows that the patients with 'gene X' are responding better to a drug, why would you continue to test patients that are not responding who do not have gene X?" Jiang asked.

Another way of conducting adaptive trials is to start out with multiple different dose arms, and then drop one or two of the most inferior treatment arms based on pre-defined rules. Jiang said this is one simple way that multinational companies can conduct adaptive global trials that not only will avoid unnecessary exposure of patients to inactive treatments, but also increases the success rate of clinical trials.

The "key difference between traditional design and adaptive design is that traditional study design is very rigorous and focused, which is good for scientific hypotheses to be tested," Jiang said, "but it is fixed and inflexible in that you do not allow new information to help you to improve the outcome of the remaining part of the study."

"If you test a new compound for lung cancer - you take all lung cancer patients that match inclusion criteria and if 20 percent of patients have tumor shrinkage and this compound has a comparable safety profile to the existing drugs, this drug may be approved," Jiang explained.

"But what we are doing very poorly is knowing what features of those 20 percent of responding patients are. As a result, doctors don't know which patients will respond and may prescribe the drugs to those 80 percent non-responders who are then exposed to an inferior treatment and potential side effects. Adaptive design can address this."

"You can only do scientific assumptions to the best of your knowledge at that point in time, and if at the interim look, for example, you see that your mortality reduction is not 10 percent as you assumed at the design stage - but 5 percent, still a clinical meaningful advantage - you should enlarge your sample size (based upon a pre-specified statistical method) so that you will have enough power to detect that 5 percent advantage."

In the past, he said, a trial would have failed, but with an adaptive design, premeditated looks at the data are allowed to allow a drug sponsor to enlarge the sample size to demonstrate the efficacy and safety of a drug while maintaining scientific integrity of a clinical trial.

For the time being, companies are not conducting adaptive trials in China, Jiang said, but it will likely happen once a few hurdles are cleared.

The biggest hurdle now is the lengthy timeline for clinical trial approval to begin Phase I-III studies, and this is the main reason that China is merely a participant in global trials and not leading the way, he said.

"We do want to invest in China - we have perhaps hundreds of different trials - but the number we can actually bring to China is only a small fraction," Jiang said. For trials that need to be completed in a year, China would miss out completely, he said, because "we just don't have time to enroll the patients."

Still, he does see progress and SFDA and CDE are "acutely aware of this issue and are doing everything they can to shorten the timelines," he said.

[Editor's note: This is part one of a two part interview; look for part two in an upcoming issue of PharmAsia News. Want to know more about growing your pipeline in Asia? Don't miss the PharmAsia Summit Oct. 26-28 in San Francisco where Frank Jiang will participate in a China R&D roundtable discussion with other pharma leaders in China. Click here for more information.]

No comments:

About This Blog

Welcome to The IN VIVO Blog, home of daily commentary on recent developments in biopharmaceutical business development, R&D, financing, marketing, and policy. Join us for discussion in the comments, or contact us via email.